SLE 临床试验结局指标的一致性和不一致性：三项 anifrolumab Ⅱ/Ⅲ 期临床试验分析。
Concordance and discordance in SLE clinical trial outcome measures: analysis of three anifrolumab phase 2/3 trials.
机构信息
Centre for Epidemiology Versus Arthritis, Division of Musculoskeletal & Dermatological Sciences, The University of Manchester, Manchester, UK.
NIHR Manchester Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
出版信息
Ann Rheum Dis. 2022 Jul;81(7):962-969. doi: 10.1136/annrheumdis-2021-221847. Epub 2022 May 17.
OBJECTIVES
In the anifrolumab systemic lupus erythematosus (SLE) trial programme, there was one trial (TULIP-1) in which BILAG-based Composite Lupus Assessment (BICLA) responses favoured anifrolumab over placebo, but the SLE Responder Index (SRI(4)) treatment difference was not significant. We investigated the degree of concordance between BICLA and SRI(4) across anifrolumab trials in order to better understand drivers of discrepant SLE trial results.
METHODS
TULIP-1, TULIP-2 (both phase 3) and MUSE (phase 2b) were randomised, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks, 48 weeks; TULIP-1/TULIP-2: n=180; MUSE: n=99) or placebo (TULIP-1: n=184, TULIP-2: n=182; MUSE: n=102). Week 52 BICLA and SRI(4) outcomes were assessed for each patient.
RESULTS
Most patients (78%-85%) had concordant BICLA and SRI(4) outcomes (Cohen's Kappa 0.6-0.7, nominal p<0.001). Dual BICLA/SRI(4) response rates favoured anifrolumab over placebo in TULIP-1, TULIP-2 and MUSE (all nominal p≤0.004). A discordant TULIP-1 BICLA non-responder/SRI(4) responder subgroup was identified (40/364, 11% of TULIP-1 population), comprising more patients receiving placebo (n=28) than anifrolumab (n=12). In this subgroup, placebo-treated patients had lower baseline disease activity, joint counts and glucocorticoid tapering rates, and more placebo-treated patients had arthritis response than anifrolumab-treated patients.
CONCLUSIONS
Across trials, most patients had concordant BICLA/SRI(4) outcomes and dual BICLA/SRI(4) responses favoured anifrolumab. A BICLA non-responder/SRI(4) responder subgroup was identified where imbalances of key factors driving the BICLA/SRI(4) discordance (disease activity, glucocorticoid taper) disproportionately favoured the TULIP-1 placebo group. Careful attention to baseline disease activity and monitoring glucocorticoid taper variation will be essential in future SLE trials.
TRIAL REGISTRATION NUMBERS
NCT02446912 and NCT02446899.
目的
在 anifrolumab 系统性红斑狼疮（SLE）试验项目中，有一项 TULIP-1 试验，该试验中基于 BILAG 的综合狼疮评估（BICLA）应答结果有利于 anifrolumab 优于安慰剂，但 SLE 应答指数（SRI(4)）治疗差异无统计学意义。我们调查了 across anifrolumab 试验中 BICLA 和 SRI(4)之间的一致性程度，以便更好地了解 SLE 试验结果不一致的驱动因素。
方法
TULIP-1、TULIP-2（均为 3 期）和 MUSE（2b 期）是随机、52 周静脉注射 anifrolumab（每 4 周 300mg，48 周；TULIP-1/TULIP-2：n=180；MUSE：n=99）或安慰剂（TULIP-1：n=184，TULIP-2：n=182；MUSE：n=102）的试验。对每位患者在第 52 周时进行 BICLA 和 SRI(4)评估。
结果
大多数患者（78%-85%）的 BICLA 和 SRI(4)结果具有一致性（Cohen's Kappa 0.6-0.7，名义 p<0.001）。在 TULIP-1、TULIP-2 和 MUSE 中，双重 BICLA/SRI(4)应答率均优于安慰剂（均为名义 p≤0.004）。在 TULIP-1 中确定了一个不一致的 TULIP-1 BICLA 无应答者/SRI(4)应答者亚组（40/364，TULIP-1 人群的 11%），该亚组中接受安慰剂治疗的患者（n=28）多于接受 anifrolumab 治疗的患者（n=12）。在该亚组中，安慰剂治疗的患者基线疾病活动度、关节计数和糖皮质激素减量率较低，接受安慰剂治疗的患者关节炎反应多于接受 anifrolumab 治疗的患者。
结论
在各试验中，大多数患者的 BICLA/SRI(4)结果具有一致性，双重 BICLA/SRI(4)应答结果均有利于 anifrolumab。在一个 BICLA 无应答者/SRI(4)应答者亚组中，驱动 BICLA/SRI(4)不一致的关键因素（疾病活动度、糖皮质激素减量）的不平衡不成比例地有利于 TULIP-1 安慰剂组。在未来的 SLE 试验中，仔细关注基线疾病活动度和监测糖皮质激素减量变化将至关重要。
试验注册
NCT02446912 和 NCT02446899。
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